1. Synthesis and In Vitro Comparison of DOTA, NODAGA and 15-5 Macrocycles as Chelators for the 64Cu-Labelling of Immunoconjugates
- Author
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Aurélie Maisonial-Besset, Tiffany Witkowski, Mercedes Quintana, Sophie Besse, Vincent Gaumet, Axel Cordonnier, Cyrille Alliot, Aurélien Vidal, Caroline Denevault-Sabourin, Sébastien Tarrit, Sophie Levesque, Elisabeth Miot-Noirault, Jean-Michel Chezal, Imagerie Moléculaire et Stratégies Théranostiques (IMoST), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA), GIP ARRONAX [Nantes], Université de Nantes (UN), GICC EA 7501, IMT (Innovation moléculaire et thérapeutique) (IMT), Groupe innovation et ciblage cellulaire (GICC), EA 7501 [2018-...] (GICC EA 7501), Université de Tours (UT)-Université de Tours (UT), Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), UNICANCER, and Ligue contre le Cancer, Comité du Puy de Dôme
- Subjects
copper-64 ,copper-64 chelating macrocycles NODAGA DOTA 15-5 trastuzumab ,[CHIM.ORGA]Chemical Sciences/Organic chemistry ,chelating macrocycles ,NODAGA ,DOTA ,15-5 ,trastuzumab ,Organic Chemistry ,Pharmaceutical Science ,[SDV.IB.MN]Life Sciences [q-bio]/Bioengineering/Nuclear medicine ,Analytical Chemistry ,Chemistry (miscellaneous) ,Drug Discovery ,Molecular Medicine ,Physical and Theoretical Chemistry ,[CHIM.RADIO]Chemical Sciences/Radiochemistry - Abstract
International audience; The development of 64 Cu-based immuno-PET radiotracers requires the use of copperspecific bifunctional chelators (BFCs) that contain functional groups allowing both convenient bioconjugation and stable copper complexes to limit in vivo bioreduction, transmetallation and/or transchelation. The excellent in vivo kinetic inertness of the pentaazamacrocyclic [ 64 Cu]Cu-15-5 complex prompted us to investigate its potential for the 64 Cu-labelling of monoclonal antibodies (mAbs), compared with the well-known NODAGA and DOTA chelators. To this end, three NODAGA, DOTA and 15-5-derived BFCs, containing a pendant azadibenzocyclooctyne moiety, were synthesised and a robust methodology was determined to form covalent bonds between them and azide-functionalised trastuzumab, an anti-HER2 mAb, using strain-promoted azide-alkyne cycloaddition. Unlike the DOTA derivative, the NODAGA-and 15-5-mAb conjugates were radiolabelled with 64 Cu, obtaining excellent radiochemical yields, under mild conditions. Although all the radioimmunoconjugates showed excellent stability in PBS or mouse serum, [ 64 Cu]Cu-15-5-and [ 64 Cu]Cu-NODAGA-trastuzumab presented higher resistance to transchelation when challenged by EDTA. Finally, the immunoreactive fraction of the radioimmunoconjugates (88-94%) was determined in HER-2 positive BT474 human breast cancer cells, confirming that the bioconjugation and radiolabelling processes implemented had no significant impact on antigen recognition.
- Published
- 2022
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